Lessons from Vioxx

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Lessons from Vioxx

• DAVID EGILMAN MD, MPH
• - Clinical Associate Professor
• - Brown University
• Amos Presler
• - Consultants to Plaintiffs in Vioxx Litigation
• - degilman_at_egilman.com
• - Linked version to actual documents can be
  found at
• http//www.vioxxdocuments.com/browse.php?displayl
  istdiregilman_arcoxia/

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Lessons from Vioxx

• COX-2s increase Mortality
• COX-2s may cause Alzheimer's
• Safety Data Unreliable
• Anti-Platelet Trial Collaborative (APTC) Strategy
• Standard Operating Procedure (SOP) was not
  standard
• Adjudications often ad hoc
• Delayed Key Data Submission

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The Big Picture(Things the Public Thinks the FDA
Considers but it Doesnt)

• What is the best way to treat RA OA?
• RA There is no evidence that NSAIDs do anything
  but treat pain. NSAIDs do not treat the
  underlying disease process.
• OA There is evidence NSAIDs makes OA worse (not
  including Cox-2 effects on fracture). 1
• Worried about GI bleeds and CV/T ?
• (Think whole patients here.)
• NSAIDs combination with PPI or H2 blocker is
  safer and cheaper than Cox-2.

1. Huskisson EC, Berry H, Gishen P, Jubb RW,
Whitehead J. Effects of anti-inflammatory drugs
on the progression of osteoarthritis of the knee.
J Rheumatol 1995221941-6.
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Placebo/Tylenol/methotrexate Long-term Trials
are Ethical

• Bombardier - 1 year placebo trial in 1999
• On the other hand, VIGOR WAS unethical
• 50 of the patients in VIGOR were on steroids.
  Scolnick wrote, this is like testing Mevacor
  for liver safety in patients with hepatitis.
• Long term placebo trials are necessary to
  establish safety there is no excuse for not
  doing them

• Arthritis Rheum. 1999 Sep42(9)1870-8. Comment
  in Arthritis Rheum. 2000 Nov43(11)2615-6.
  Function and health-related quality of life
  results from a randomized controlled trial of
  leflunomide versus methotrexate or placebo in
  patients with active rheumatoid arthritis.
  Leflunomide Rheumatoid Arthritis Investigators
  Group. Strand V, Tugwell P, Bombardier C, Maetzel
  A, Crawford B, Dorrier C, Thompson A, Wells G.
  MRK-NJ0130089

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The Big Picture

• Evaluation MUST consider
• Number Needed to Treat to Harm/Help

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Arcoxia Less Safe than Comparators
From Mercks Arcoxia Briefing Document

• More Hypertension Pg 155-63
• More Renal complications Pg 162
• More CHF Pg 142
• More Strokes Pg 163
• More MIs Pg 164
• More Arrhythmias Pg 93
• (Despite the fact that Arrhythmias were
  retroactively deleted from adjudication event
  list.)

FDA Arthritis Drug Advisory Committee Meeting,
ARCOXIA (Etoricoxib 30 and 60 mg For Symptomatic
Treatment of Osteoarthritis.Briefing Document
(Background Package) April 12,2007.
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CHF Adjudicated Post Hoc for EDGE after
Freezing (Un-blinding)

• FDA says Development of Congestive Heart
  Failure (CHF) CHF was handled similarly to the
  CV and GI events with an adjudication committee.
• NOT TRUE
• Merck deleted CHF (atrial Fib) from list of
  events to be adjudicated Dec 1999 (post dated Oct
  3).
• Merck added CHF to ADJ event list around 12/2006
• This data is unreliable since the CHF data was
  not collected systematically throughout the
  trials.

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More Deaths on COX-2 Treatment
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COX-2 Increase Mortality Effects are complex

• Merck claims AD deaths should be ignored because
  theres no pattern.

• Pattern excess deaths were a result of selective
  Cox-2 blocking and accidents due to AD
  conversion.
• Pneumonia Cox-2 is part of response to
  infection.
• GI Bleed deaths Cox-2 needed for ulcer healing.
  
• AD patients have increased rates of accidental
  deaths.

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COX-2s Increase Mortality

• Death Warning Needed on Label for Arcoxia

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COX-2s may cause Alzheimers Disease
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COX-2s may cause Alzheimers (AD)

• Relative Risk of AD Conversion Vioxx/Placebo
• Trial would have been stopped by a DSMB, but
  Merck eliminated the DSMB from the protocol.

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COX-2s may cause Alzheimers Disease

• AD Warning Needed on Label for Arcoxia Class
  Effect
• Cox-2 drugs should have a warning that states
  that studies have found a relationship between
  use and conversion to AD.

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Unreliable Safety Data Manipulating the
Standard Operating Procedure (SOP)
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Unreliable Safety Data Manipulating the
Standard Operating Procedure (SOP)
Lots of SOP changes most are post hoc follow
changes in practice.
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Unreliable Safety Data MANIPULATING THE SOP

• CV SOP has No Cut-off Rule for CV Events

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Unreliable Safety Data MANIPULATING THE SOP

• Study was un-blinded and results were distributed
  3-9-2000. Bad CV data.

SOP 14 Day CV cut off Rule comes later.
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MRK-NJ0121088
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Unreliable Safety Data RETROACTIVE CHANGES OF
SOP
CHF and PUMONARY EDEMA GONE - 21 DELETIONS
12/1999
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Unreliable Safety Data MANIPULATING THE SOP

• SOP re-written to match procedures

2003 Chen memo regarding serious AEs eligible
for adjudication, I used the following wording in
my DAP Serious adverse experiences eligible for
adjudication include All deaths, including
all-cause mortality events and deaths not
eligible for inclusion in the all-cause mortality
analyses Serious adverse experiences that the
clinical monitors feel may potentially be
thromboembolic, even though the
investigator-reported terms would not normally be
eligible for adjudication (e.g., a case with a
term of "neurological disorder"). Could you
confirm that bullet 3 was actually done for the
AD studies? If not, Ill simply delete it.
Emphasis added
Could you confirm that bullet 3 was actually
done for the AD studies? If not, Ill simply
delete it.
Chen, J. Email communication, Examples of
spreadsheets for internally adjudicated confirmed
safety endpoints for Vioxx ad. MRK-AFV0210573.
May 28, 2003.
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Unreliable Safety Data Lots of Post Hoc SOP
Changes

• Standard Operating Procedure for the
  Surveillance, Monitoring, and Adjudication of
  Acute Thrombotic and Embolic Vascular Events and
  Deaths in Clinical Trials of COX-2 Specific
  Inhibitors
• Revised 16-February-1999
• Revised 30-August-1999
• Revised 17-September-2003
• Revised 22-August-2005
• Revised 22-February-2006

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Unreliable Safety Data CHF under reported
CHF is serious by definition if it was a
diagnosis that was Eligible for Adjudication.
Catch 22 Merck deleted CHF post hoc from list of
eligible events.
See Arcoxia transcript page 161. MRK-AQZ0039486
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Unreliable Safety DataCHEATING ON
ADJUDICATIONS and MANIPULATION OF INDIVIDUAL
CASES
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Unreliable Safety DataCHEATING ON ADJUDICATIONS

• AN 0158 Alzheimer's Trial

Barr
Reported to FDA as insufficient data to
adjudicate on VIOXX
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Unreliable Safety DataCHEATING ON ADJUDICATIONS

• Merck adjudication loses more Vioxx cases than
  Placebo cases it happens study after study.

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Unreliable Safety Data Biased adjudication

• Vioxx cases confirmed less often than placebo
  cases ss 1998-2000.
• Vioxx label only included data through March 16,
  2001.
• Study 078 was not supposed to be adjudicated.

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The Big Picture Vioxx Lessons

• Arcoxia Evaluation MUST consider
• Number Needed to Treat to Harm/Help
• If approved warnings Must be Explicit

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Out-takes of Mercks Vioxx Video News Release

• Dr. Laine claims Merck broadcasted bogus
  information
• Merck repeated this bogus information in the
  Arcoxia ACM.
• No evidence Arcoxia reduces hospitalizations for
  GI bleeds and serious PUBs.

AVI1
135
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Out-takes of Mercks Vioxx Video News Release

• Transcript
• Interviewer You know, lets just take another
  quick crack at the hospitalizations for the VNR,
  alright?
• Dr. Laine And the reason I actually think is
  because those numbers, by the way, that people
  use are totally incorrect, and theyre based on
  just extreme, totally incorrect umm data.
• Interviewer But we keep using them.
• Dr. Laine No. Everybody uses them because they
  sound good.
• Indistinct Comment from Interviewer
• Dr. Laine No, they sound good, but I mean, well
  its the same person who keeps putting them out.
• Interviewer Oh, I see.
• Dr. Laine But I mean I have recalculated also,
  so the only way you can do it is subtract those
  who do from those who dont, and that number
  doesnt take it into account. So to say its due
  to NSAIDs is also incorrect. So theres about
  five different reasons why those numbers are
  totally bogus, but umm, I agree, its in the,
  its out there in the umm common realm and
  everybody uses those numbers. Yeah, I know,
  because its a very impressive sound-byte.

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Out-takes of Mercks Vioxx Video News Release

• Transcript
• Interviewer Does it help that were using the
  word associated with NSAIDs? Does that sort of,
  water it down a little bit?
• Dr. Laine No, I mean because the issue is umm
  part of the issue is the umm you just dont have
  any idea. Im not saying its actually wrong. The
  death-rate is probably wrong. The
  hospitalizations prob-, may be right. Umm, just
  the death rates probably wrong, but umm anyway.
• Interviewer Alright, lets, lets
• Dr. Laine But as long as we say its estimated,
  or reported its, its not me saying it, so

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Out-takes of Mercks Vioxx Video News Release

• Dr. Laine claims We were cagey in how we
  published the data.

AVI2
139
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Out-takes of Mercks Vioxx Video News Release

• Transcript
• Interviewer What were the renal findings in the
  study?
• Dr. Laine Well, umm, thats actually not going
  to be, I mean the only thing thats in the New
  England journal article, says theres no
  difference in renal failure, or renal
  dysfunction. So I dont think you really want to
  go there, do you? Because, there are no data on
  blood pressure or hypertexcuse me, blood
  pressure or edema in the study. And the only
  thing it says specifically, and we were cagey
  about this, was related to renal failure, renal
  dysfunction. And thats not what youre looking
  at, so, I mean I would actually take that out,
  because I think you dont, no I mean I would just
  suggest that anything you do, just as an aside,
  Im gonna talk to Alise in about an hour, but you
  dont wanna talk about that because if you start
  bringing up hypertension and edema its nowhere
  in the study, so if you bring it up its not
  whats in the article.
• Interviewer I agree, I agree.
• Dr. Laine Okay.

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